Biological phosphate fulfills a central role in energy-transduction manifolds as well as biosynthetic and cellular signaling pathways in both prokaryotic and eukaryotic organisms. In spite of this fundamental role for phosphorylated biomolecules in cellular processes, significant limitations are encountered by those studying these pathways due to the unique charged nature of both the intermediates and the mimics historically employed as molecular probes of these processes (Knowles, J. R. Ada Doisy Lecture, University of Illinois at Urbana-Champaign, 1985). The paradox surrounding phosphate remains: The unique anionic character of biological phosphate and the controlled lability of this functional group remain the crux of cellular energetics and regulation; nonetheless, these very molecular properties are the essence of the challenges faced by those seeking to understand a multitude of cellular processes at the molecular level as well as those endeavoring to impact clinical outcomes. Through integrated design considerations disclosed herein, these mechanistic chemistries, biophysical properties and mimicries of biological phosphorylation may serve as the three-fold basis of a fundamental approach towards small molecule interrogations of these biological processes and the resultant medical interventions.
A novel, specific and physiologically stable mimic of this key biological switch would greatly enhance multiple approaches towards a more complete understanding of cellular processes surrounding phosphorylated intermediates and compounds. Such a specific biological probe would serve as a powerful research tool at the molecular level and as a potential gateway entry into the fields of diagnostic reporters and pharmaceuticals at the level of the entire organism. Multiple techniques for evaluation of such an appropriate probe would be enhanced by the unique atomic characteristics of a well-designed and specific mimic. Increased bioavailabilities may directly correspond with enhanced sensitivities in diagnostic settings, while higher potencies and greater selectivities at specific targets and receptors may be realized in clinical pharmaceutical applications.
The transient, selective and site-specific covalent attachment of a phosphate group to various biological molecules is one of the most (if not the) fundamental mechanisms of cellular regulation at the molecular level (Dzeja, P. P. and Terzic, A. J Exp Bio 206: 2039 (2003)). The potential of this isosteric replacement to positively impact clinical outcomes in the context of cell signaling processes, energetic transformations, ion channel regulation, cell cycle regulation, lipid metabolism, saccharide metabolism and processing, cytoskeletal regulation, DNA and RNA analoging as well as nearly all other biologically relevant phosphate binding events is a fundamental extension of the isostere's molecular design. Furthermore, impact upon the structural role phosphorous plays in bone and tooth development, metabolism and degradation processes is a further contemplated application of the disclosure.